Targeting Fate-Decision Circuitry of Pathogens to Develop Novel Anti-viral Therapeutics

Weinberger Lab

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Most antivirals attack a virus's proteins directly, which leaves them prone to the resistance and toxicity that limit so many treatments. We take a different approach: by mapping the gene-regulatory circuits that govern a virus's fate decisions, we can target those circuits rationally and disrupt infection in ways that are far harder to escape. The examples below show this strategy at work in two pathogens, using noise-modulating molecules to reactivate latent HIV and feedback disruptors to create escape-resistant therapies against cytomegalovirus.

HIV

Harnessing stochastic gene-expression noise to reverse HIV latency and purge the latent reservoir, the primary barrier to a cure.

For HIV, stochastic noise is now recognized as a major driver of HIV latency in patients (Ho et al., 2013; Rouzine et al., 2014; Weinberger and Weinberger, 2013). Purging the latent reservoir, which requires ‘reversing’ latency, remains the primary barrier to curing HIV.

We predicted that noise could be exploited to promote reactivation of latent HIV. This led to the discovery of a class of noise-enhancing and noise-suppressing molecules (Dar et al., 2014). We subsequently discovered the molecular mechanism of action for a class of these noise-enhancer molecules (Desai et al., 2021).

These noise-enhancer molecules synergize with conventional transcriptional activators and increase their activity, promoting increased latent reactivation (Fig. 2B, below). As FDA-approved compounds, noise enhancers have potential therapeutic application to HIV and possibly other clinically relevant cell-fate decisions.

**Exploiting “noise” for cell-fate manipulation.** Identification of small molecules that enhance noise in HIV gene expression. Each point represents flow cytometry analysis of 50,000 cells exposed to a compound; 1,600 FDA-approved compounds are shown.

Cytomegalovirus (CMV): A major unmet medical need

Targeting the viral 'accelerator' circuit to develop a first-in-class, escape-resistant therapy against a leading cause of birth defects and transplant deaths.

CMV is the leading known cause of birth defects—causing more birth defects than Down’s syndrome, fetal alcohol syndrome, or spina bifida—and death in transplant recipients (Cannon, 2009). Existing CMV treatments are highly toxic and resistance-prone. By screening for disruptors of CMV’s accelerator circuit (Teng et al., 2012), we identified first-in-class ‘escape-resistant’ therapeutic approach (Chaturvedi et al., 2022).

(A) The CMV IE2 protein is one of the first expressed CMV proteins upon infection and reactivation from latency. IE2 is an obligate transactivator of CMV early genes. However, IE2 is also highly cytotoxic at high levels and must auto-repress its own promoter, the Major Immediate Early Promoter (MIEP), to form a highly cooperative negative-feedback circuit that limits expression. (B) This highly cooperative IE2 negative feedback allows accelerated IE2 kinetics but precludes IE2 levels from increasing to levels where IE2 could be cytotoxic (i.e. acts as an accelerator, blue). (C) Accelerating IE2 yields a fitness advantage while disrupting IE2 feedback amplifies IE2, causing substantial cytotoxicity to the host cell and reducing viral output > 100-fold. (Adapted from Teng et al., Cell, 2012)

(Research from the above page is included in US patent application #2014127148)